Sighted people have circadian (daily) rhythms that are synchronized to the 24-hour light/dark cycle. More than half of all totally blind people (those with no light perception) have "free-running" circadian rhythms that cannot synchronize to the 24-hour day. We call these people "blind free-runners" (BFRs). Their sleep and mood disturbances are often a burden second only to not having vision. The long-term goal of our laboratory has been to understand how to best use the daily rise in plasma and saliva melatonin levels as a marker for the body clock, in order to diagnose and treat body clock disorders. In addition to developing bright light exposure as the treatment of choice for patients with seasonal affective disorder (SAD), we have been developing oral melatonin as the treatment of choice for BFRs. We have found that a low, physiological dose of melatonin taken daily can synchronize their free-running rhythms to the 24-hour day. In the course of our work, we have recently discovered that as-yet-unidentified time cues in the natural environment can profoundly affect the circadian rhythms of BFRs, although they are usually too weak to synchronize them to the 24-hour day. Our first specific aim is to precisely characterize the effects of these weak time cues in BFRs, which may lead to their identification that could therefore eventually be used in the treatment of body clock disturbances of both blind and sighted people. Our second specific aim is to determine the lowest (and therefore safest) doses of melatonin that are able to synchronize BFRs when taken at 6 p.m. (the administration time that results in synchronization to the same time of the day as in sighted people) compared to bedtime (a more convenient time to remember to take a medication). Since melatonin in higher doses is often taken at bedtime to take advantage of its sleepiness side effect, specific aim three will test the highest doses that can optimally be taken at bedtime by BFRs. Specific Aims 2 & 3 will together describe the full range of melatonin doses that can be helpful to blind people. These treatment regimens should also be helpful to sighted people, particularly the lowest doses for individuals who want to take a medication that produces the same levels in the blood that naturally occur each night - which can be used to shift the body clock earlier (when taken just before the natural rise in melatonin levels in the evening) or shift the clock later (when taken just after the natural fall in melatonin levels in the morning). [unreadable] [unreadable] [unreadable]